There are more than 120 members of the genus Mycobacterium, which are diverse in pathogenicity, in vivo adaptation, virulence, response to drugs and growth characteristics. Mycobacterial diseases are caused by organisms of the Mycobacterium tuberculosis Complex (MtbC) like Mycobacterium tuberculosis (Mtb), Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetii and Mycobacterium microti. Mycobacteria other than MtbC and Mycobacterium leprae are known as non-tuberculous mycobacteria (NTM) and can cause also human and animal diseases as is the case for Mycobacterium avium complex (MAC), Mycobacterium smegmatis, Mycobacterium gordonae, Mycobacterium kansasii, Mycobacterium terrae, Mycobacterium scrofulaceum, Mycobacterium vaccae, Mycobacterium marinum, Mycobacterium lentiflavum, Mycobacterium fortuitum, Mycobacterium chelonae and Mycobacterium abscessus. 
Most human tuberculosis (TB) is caused by Mtb but some cases are due to Mycobacterium bovis, which is the principal cause of tuberculosis in cattle and many other mammals, or Mycobacterium africanum. 
The consequences of tuberculosis on all human societies are dramatic: worldwide, one person out of three is infected with Mtb.
The lung is the main entrance gate of Mtb in the body and, consequently, TB is primarily a disease of the lungs. Mycobacterium tuberculosis causes a focal infection in the site where it is deposited after inhalation. If the infection cannot be contained at the local level, bacilli dissemination is produced initially by hematogenic route, probably inside phagocytic cells, towards different organs and, eventually, to the contiguous pleura. It reaches hilar lymph nodes via the lymphatic route, and from there, a second systemic dissemination can occur, through the thoracic duct and superior vena cava, with the development of local foci in the lungs. Extrapulmonary foci can also be produced by hematogenic and lymphatic dissemination. Tuberculosis can proceed to a generalized infection (“miliary tuberculosis”).
The clinical manifestations of TB depend on the local organic defenses on the sites of bacilli multiplication. Primary TB infection occurs commonly during childhood and most of the times, causes no apparent symptoms and stays latent for life or until reactivation. Occasionally cause malaise, low-grade fever, erythema nodosum and phlyctenular conjunctivitis. In seriously immunodepressed patients it can develop into a disseminated form, which is sometimes fatal. Miliary tuberculosis results from the massive hematogenic dissemination of Mtb during the primary infection.
The development of clinical TB will occur in 5%-10% of infected persons at some point in their lives. The existence of post-primary TB, also known as secondary TB, means that the infection can progress after the development of an adequate specific immune response. This TB episode can develop in two ways: by inhalation of new bacilli or by reactivation of the primary focus.
There are factors involved in increased risk of developing TB, of which the most important are those interfering directly with host immunity. Diseases and conditions that weaken immunity, such as malnutrition, alcoholism, illicit drug abuse, advanced age, human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS), diabetes mellitus, gastrectomy, chronic renal insufficiency, chronic liver disease, silicosis, paracoccidioidomycosis, leukemias, solid tumors, prolonged treatment with corticosteroids, immunosuppressive drug treatments, organ transplant, systemic lupus erythematosus, treatment with anti-tumor necrosis factor (TNF) antibodies and hereditary features, are factors that facilitate the development of TB disease. In industrialized countries the increased survival rates have resulted in larger elderly populations with an increased risk of reactivation of the infection. Tuberculosis in the elderly may be due also to a newly acquired infection. Congenital TB is considered a rare event in the whole spectrum of TB presentations. This infection is caused by lymphohematogenous spread during pregnancy from an infected placenta or aspiration of contaminated amniotic fluid.
Additional factors include the infective bacterial load, virulence of Mtb and host genetic susceptibility.
Pulmonary TB is the most common form of post-primary disease. The natural evolution of post-primary lesions in immunocompetent persons can lead to dissemination and death in about 50% of cases, and to chronicity in about 25% to 30%.
After penetration into the organism through the respiratory route, Mtb can multiply in any organ during the primary infection, before development of the specific immune response. After this, tubercle bacilli can multiply at any time when there is a decrease in the host's immune capacity to contain the bacilli in their implantation sites. The extrapulmonary tuberculosis can affect any other organ of the body, including lymph nodes, pleura, genitourinary system, central nervous system, osteoarticular system, gastrointestinal system, skin and soft tissues and eye.
Tuberculosis accounts for 2.5% of the global burden of disease and holds the seventh place in the global ranking of causes of death. In 2010, there were 8.8 million incident cases of TB, 1.1 million deaths from TB among HIV negative people and an additional 0.35 million deaths from HIV-associated TB. Without treatment, a person with active TB will infect an average of 10 to 15 other people per year.
The minimum period of treatment for active, drug-sensitive TB is 6 months, and will typically use a starting regimen of four drugs denominated first-line drugs: isoniazid (INH), rifampicin (RMP), pyrazidamine (PZA) and ethambutol (EMB). However, when administered in real-world settings, the regimen's flaws become apparent. Treatment of drug-resistant TB is even lengthier, taking 18-24 months or longer.
The selection of the drug regimen must be done considering at least the following factors: disease localization and severity, result of sputum smear microscopy, HIV co-infection, prevalence of drug resistance in the setting, availability of drugs, cost of treatment and medical supervision, whether the patient has previously received any anti-tuberculosis drug, the country's budget, health coverage by public health services and qualifications of health staff.
Human immunodeficiency virus infection has clearly had a profound effect on TB epidemiology. Human immunodeficiency virus infection is a potent risk factor for TB and both form a lethal combination, each speeding the other's progress. Not only does HIV increase the risk of reactivating latent Mtb and the risk of rapid TB progression soon after Mtb infection or reinfection. Those who have latent tuberculosis have a 10% lifetime risk of progressing to active infection, with half (5%) occurring within 1-2 years after initial infection. In persons co-infected with Mtb and HIV, however, the annual risk can exceed 10%.
The resistance mechanisms can be divided in natural and acquired. The natural drug resistance of Mtb is an important obstacle for the treatment and control of TB. This resistance has traditionally been attributed to the unusual multi-layer cell envelope and/or active multidrug efflux pumps.
The acquired drug resistance is mediated by mutations in chromosomal genes. So far, no single pleiotropic mutation has been found in Mtb to cause a multi-drug resistant (MDR) phenotype. The MDR phenotype is caused by sequential accumulation of mutations in different genes involved in resistance to individual drugs, due to inappropriate treatment or poor adherence to treatment. However, it is important to observe that some resistant strains do not present these classic mutations, suggesting the possibility of the existence of other mechanisms such as efflux pumps and alterations in the permeability of the cell wall.
Multidrug-resistant TB (MDR-TB) is defined by resistance to the two most commonly used drugs in the current four-drug (or first-line) regimen, INH and RMP. According to the World Health Organization (WHO), Eastern Europe's rates of MDR-TB are the highest, where MDR-TB makes up 20 percent of all new TB cases. During the late 1980s and early 1990s, outbreaks of MDR-TB in North America and Europe killed more than 80% of those who contracted the disease. Today, MDR-TB is also quite common in India and China, as the two countries combined account for more than half of the global MDR-TB burden.
Drug-resistant TB is the man-made result of interrupted, erratic, or inadequate TB therapy, and its spread is undermining efforts to control the global TB epidemic. Multiple drug resistant and extensively drug resistant tuberculosis (XDR-TB) develop when the long, complex, decades-old TB drug regimen is improperly administered, or when people with TB stop taking their medicines before the disease has been fully eradicated from their body. Once a drug-resistant strain has developed, it can be transmitted directly to others just like drug-susceptible TB.
Treatment for MDR-TB consists of what are called second-line drugs. These drugs are administered when first-line drugs fail. Treatment for MDR-TB is commonly administered for 2 years or longer and involves daily injections. Many second-line drugs are toxic and have severe side effects. Further, the cost of curing MDR-TB can be staggering—literally thousands of times as expensive as that of regular treatment in some regions—posing a significant challenge to governments, health systems, and other payers.
More recently emerged extensively drug-resistant Mtb strains that are the agents of extensively drug-resistant tuberculosis (XDR-TB). This form of the disease is defined as TB that has developed resistance to at least RMP and INH, as well as to any member of the quinolone family and at least one of the following second-line anti-TB injectable drugs: kanamycin (KAN), capreomycin (CAP) or amikacin (AMIC).
In recent decades the development of MDR-TB and XDR-TB, and the presence of HIV have combined to increase the global threat to public health posed by TB. In addition to increasing individual susceptibility to TB following Mtb infection, a high burden of HIV-associated TB cases also expands Mtb transmission rates at the community level, threatening the health and survival of HIV-negative individuals as well. In several countries, HIV has been associated with epidemic outbreaks of TB. Many of the reported outbreaks involved MDR strains, which respond poorly to standard therapy—the growing burden of TB.
The long and complex regimen is burdensome for patients, even when taken under direct observation by a healthcare worker or community member, as recommended by WHO. As a result, many patients do not or cannot complete their treatment, which leads to the development of drug-resistant strains. While MDR-TB is a man-made issue, research has shown that those strains are now being transmitted from patient to patient. Second-line drugs are also much more toxic and considerably more expensive than the standard first-line anti-TB regimen.
Furthermore, current first-line treatment regimens are not compatible with certain common antiretroviral (ARV) therapies used to treat HIV/AIDS. To avoid drug-drug interactions in co-infected patients, the treatment regimen for one of the diseases must be suboptimally modified. Therefore, new drugs are needed that will be effective in treating children, and latent TB infection (an asymptomatic infection) and will be compatible with antiretroviral therapy. Additionally, new regimens need to be affordable and easily managed in the field.
The introduction of new drugs, preferably with novel mechanisms of action, which will be active against current drug-resistant and extensively drug-resistant strains, and fewer TB drug side effects, will hopefully allow for a shorter TB regimen for both drug-sensitive and drug-resistant disease (MDR-TB and XDR-TB). Shortening treatment to four or two months or even less should increase cure rates, improve patient adherence, and lessen the likelihood of developing drug resistance. This poses a massive challenge to controlling these twin epidemics, given that an estimated one-third of the 40 million people living with HIV/AIDS worldwide are co-infected with TB. The deadly synergy of these two diseases demands first-line treatments that can be fully harmonized.
Drug-resistant TB is difficult, complicated, and expensive to treat. Treatment relies on second-line drugs, and is commonly administered for 2 years or longer. It includes daily injections, and often causes severe side effects. Of those who do, nearly half will still die. What's worse, some resistant strains are virtually untreatable with any existing antibiotics. The complexity and prohibitive cost of MDR-TB treatment means that fewer than 3% of the world's MDR-TB patients receive proper treatment. Without a significantly simpler, faster cheaper, oral treatment for MDR-TB, countries cannot scale up treatment to serve their populations. Without new, simple, and affordable treatments for MDR-TB, this is not realistically possible.
Extensively drug-resistant TB (XDR-TB) is emerging as an even more ominous threat. This makes XDR-TB treatment extremely complicated, if not impossible, in resource-limited settings. It is estimated that 70% of XDR-TB patients die within a month of diagnosis. The most recent drug-resistance surveillance data issued by the WHO estimates that an average of roughly 5 percent of MDR-TB cases are XDR-TB.
When drug resistance develops, patients should be treated with a new combination containing at least three drugs that they had never received before (or that do not show cross-resistance with those to which resistance is suspected). In these conditions, the treatment is longer, more toxic, more expensive and less effective than regimens containing first-line drugs, and should be directly observed.
Since HIV/AIDS patients have a higher probability of acquiring TB (either pulmonary or extrapulmonary) or other mycobacterial opportunistic infections, particular drug regimens have been designed for treating active TB disease in them.
Also, the severity of adverse effects of antimycobacterial drugs (due to the interactions with anti-retroviral drugs) and mortality is higher among HIV-positive patients. Although, in general, HIV-positive patients respond well to a standard short-course treatment of TB, treatment failure due to malabsorption of antimycobacterial drugs has been reported. For example, rifamycins (rifampicin, rifabutin, etc.) have clinically relevant interactions with some drugs used in the antiretroviral therapy, since they induce the metabolism of antiretroviral agents such as zidovudine, non-nucleoside reverse transcriptase inhibitors, and HIV protease inhibitors, whose concentrations may fall to sub-therapeutic levels. Then, rifamycin-free regimens have been suggested. They consist of INH, EMB, PZA, and streptomycin (SM), daily for two months, followed by INH, PZA, and SM two or three times weekly for seven months. However, it has also been described that the use of RIF throughout antituberculosis treatment improves outcome in HIV patients.
Chemoprophylaxis of TB is indicated for asymptomatic patients having a positive tuberculin skin test (TST) but not showing active disease (latent TB infection), especially when they are at risk of the disease (for example, HIV positive patients). Prophylaxis is most frequently achieved by the administration of INH only, at doses of 300 mg daily for six to nine months (although there is a risk of developing INH resistance). When resistance to INH is suspected, other regimens including RIF, PZA or EMB can be administered, although there is a greater chance of having adverse effects. In TB prophylaxis, RIF can be given concurrently with INH, reducing the prophylaxis treatment to three months.
Most drugs used in antituberculosis treatment (isoniazid, rifampicin, rifapentine, rifabutin, pyrazinamide, ethambutol and ethionamide) are commercially available as tablets or capsules and can therefore be taken orally. Isoniazid is also available as an elixir, in granules for pediatric use, and in aqueous solution for intravenous or intramuscular injection. Rifampicin is available in powder for preparing suspensions for oral administration, and also in aqueous solution for intravenous or intramuscular injection. The exceptions are the aminoglycosides (streptomycin, kanamycin, and amikacin) and capreomycin, which are only available as aqueous solutions for intravenous or intramuscular injection. Para aminosalicylic acid (PAS) is usually available as granules for mixing with food; tablets and solutions for intravenous administration can also be found. The fluoroquinolones are available as tablets or as aqueous solutions for intravenous injections.
Isoniazid, rifampicin and pyrazinamide can also be found in fixed-dose combination preparations. When available, the use of combination preparations is recommended. Indeed, by reducing the number of tablets to be taken, they facilitate the patient's adherence to treatment and supervision of therapy. Most importantly, this form of preparation minimizes the possibility of monotherapy and therefore, reduces the risk of drug resistance development.
The framework of mycobacterial infections and diseases all over the world requires the systematic search for new antimycobacterial drugs. Almost no new antimycobacterial drug classes have been developed over the last 40 years. In fact, once the industrialized countries felt confident in accomplishing TB control, the leading pharmaceutical industries lost interest in the development of antimycobacterial drugs.
The emergence of the HIV pandemic soon followed by the increase of MDR-TB and XDR-TB incidence rate, the prevalence of chronic diseases, the generalized use of immunosuppressive treatments, the increase in organ transplantation and the general increase of the prevalence of severe and moderately severe forms of immunodeficiency conditions in the population require an urgent investment in research and development to discover new candidate compounds to treat the drug-resistant TB, overcome the complex drug-drug interactions between antimycobacterial and antiviral or cytotoxic drugs.
Additionally, these efforts should be focusing in the development of a shorter and simpler regime for TB could improve treatment compliance, stop the spread and enable the global scale-up of MDR-TB and XDR-TB treatment. A shorter and simpler treatment will not only help cure those currently under care, but will also allow health workers to reach more people by reducing the burden on national TB programs.
The research and development of new medicines is an integral part of a comprehensive TB control plan. Without new and improved TB treatment regimens, including treatment for those suffering from MDR-TB and co-infected with HIV/AIDS, the reduction and eventual eradication of the disease cannot be achieved.
The nontuberculous mycobacteria (NTM) are for the most part ubiquitous environmental organisms found in soil and water that only rarely cause disease in humans. There are numerous species of NTM. Although regional variation in species isolation has been shown, the NTM most frequently isolated are those of the Mycobacterium avium Complex (MaC)—Mycobacterium intracellulare and Mycobacterium avium, Mycobacterium smegmatis, Mycobacterium kansasii, Mycobacterium fortuitum, Mycobacterium abscessus and Mycobacterium chelonae. 
These organisms have significant structural and biochemical similarities with Mtb. Because they are of significantly lower pathogenicity than Mtb, they are considered opportunistic pathogens. NTM are an important cause of morbidity and mortality, often in the form of progressive lung disease. Several species are associated with diseases of other organs or systems (ex.: skin and soft tissue, lymphatic and gastrointestinal systems). Disseminated disease due to NTM is primarily associated with AIDS and other forms of severe immunosuppression.
Human immunodeficiency virus infection also increases the risk of disease mediated by NTM. Patients with AIDS require new treatment modalities to approach MaC disease and prevention, such as combination therapy with nucleoside reverse transcriptase inhibitors and HIV protease inhibitors, as well as antimycobacterial prophylaxis. Most of the NTM except Mycobacterium kansasii are inherently resistant or partially susceptible to the standard anti-tubercular drugs.
Drug therapy for MAC disease involves multiple drugs; therefore, the risk of adverse drug reactions and/or toxicities is relatively high. In addition, the optimal therapeutic regimen has yet to be established. The recommended initial regimen for most patients with fibrocavitary or nodular/bronchiectatic MaC lung disease is a three times weekly regimen including clarithromycin or azithromycin, ethambutol and rifampin administered three times per week. Patients respond best to MaC treatment regimens the first time they are administered; therefore, it is very important that patients receive recommended multidrug therapy the first time they are treated.
The management of macrolide-resistant MaC involves complex clinical decision making, drug choices, and protracted duration of therapy, analogous to the drug management of MDR-TB.
Multiple factors can interfere with the successful treatment of MaC lung disease, including medication nonadherence, adverse events, prior therapy of MaC lung disease, lack of response to a medication regimen, or the emergence of a macrolide-resistant MaC strains.
The Mycobacterium leprae (Mlp) is the etiologic agent of leprosy, a chronic mycobacterial disease characterized by the involvement primarily of skin as well as peripheral nerves and the mucosa of the upper airway. The organism has never been grown in bacteriologic media or cell culture, but has been grown in mouse foot pads. The risk groups are the close contacts with patients with untreated, active, predominantly multibacillary disease and persons living in countries with highly endemic disease.
In 2002, Brazil, Madagascar, Mozambique, Tanzania, and Nepal had having 90% of cases. Worldwide, 1-2 million persons are permanently disabled as a result of leprosy. However, persons receiving antibiotic treatment or having completed treatment are considered free of active infection.
Multidrug therapy has not been implemented in many endemic areas. Nerve damage must be recognized and managed. Relapse rate after completion of short course multidrug therapy may rise.
Paucibacillary leprosy should be treated for 6-12 months with dapsone plus rifampin. This regimen should be followed by treatment with dapsone as monotherapy for 3 years in patients with tuberculoid leprosy or 5 years in patients with borderline lepromatous leprosy. Multibacillary leprosy should be treated for months with dapsone 100 mg/day, clofazimine 50 mg/day and rifampin 600 mg plus clofazimine 300 mg/month. Increasing resistance in patients treated for leprosy has been reported in Southeast Asia. The drug most commonly found to be resistant is dapsone, often in the context of prior exposure or treatment attempts with monotherapy.
More effective and safer compounds should allow simpler and shorter multiple-drug regimes, with a reduced risk of interactions with HIV/AIDS drug treatment or with immunosuppressive and cytotoxic drugs. The development of drug-resistant strains is a continuous biological process, accelerated by the noncompliance with the available regimes and the increase of moderately severe and severe forms of imunodepression in low- and high-income countries. The treatment and prevention of diseases caused by microorganisms of the Mycobacterium genus (e.g., Mycobacterium tuberculosis, nontuberculous mycobacteria and Mycobacterium leprae) requires, urgently, an investment in the research and development of new compounds.
Therefore, the technical problem solved in the present invention is to provide further pharmaceutical active compounds for the prevention and treatment of tuberculosis as well as diseases caused by nontuberculous mycobacteria or caused by Mycobacterium leprae. Surprisingly, the inventors have found that the compounds of formula I are effective in the prevention and treatment of tuberculosis, diseases caused by nontuberculous mycobacteria and/or caused by Mycobacterium leprae. 